Molecular Pharmacology, Vol 20, 423-428, Copyright © 1981 by the American Society for Pharmacology and Experimental Therapeutics

Molecular Orbital Studies of the Metabolism of Fluroxene and Analogous Fluorinated Ether Anesthetics

¹ Division of Laboratories and Research, New York State Department of Health, Albany, New York 12201

Semiempirical molecular orbital calculations (by the modified neglect of diatomic overlap method) have been performed on the anesthetic fluroxene (2,2,2-trifluoroethyl vinyl ether, TFVE) and its analogues 2,2,2-trifluoroethyl allyl ether (TFAE) and ethyl vinyl ether to gain insight into the hepatic microsomal cytochrome P-450-catalyzed metabolism and suicide substrate functions of the ethers. The calculations indicate that the metabolic intermediate epoxides of both TFVE and TFAE require significant activation energy for ring opening. For TFVE, however, only protonation removes this energy barrier to ring opening (consistent with experimental observation). These calculated energy differences explain why TFVE metabolism can result in simultaneous product formation and destruction of the catalyzing enzyme through selective protonation. Calculated heats of reaction indicate that TFVE metabolism probably occurs via an intermediate tetrahedral hemiacetal. The calculated electronic structures of TFVE and TFAE, by providing data on the reactive sites on the molecules, have yielded insight into the mechanisms of cytochrome P-450 function.